Biology of Liver and Pancreatic Development and Disease

Most common disorders of western society have multifactorial causes and result from a combination of genetic and environmental influences. Many of those disorders are secondary to dysregulation of lipid and glucose metabolism that leads to the so called “metabolic syndrome” of obesity, diabetes, cardiovascular problems and fatty liver disease. Although there are clear environmental causes such as western diet and alcohol, some individuals and population groups are more likely to develop severe clinical illness than others.

Liver and pancreas are the key “metabolic organs” producing hormones and enzymes that govern the complex regulation of lipid and carbohydrate metabolism, thus investigation of the regulatory systems of these organs will advance the knowledge of metabolic homeostasis and may give insights that could lead to improved health in Europe. Previous work by BOLD partners showed that a set of specific transcription factors (TFs) – hepatocyte nuclear factors (HNFs) - are required in development and normal function of liver and pancreas. The effect of abnormalities which result from defects in these factors may be dose-dependent, thus although their complete absence results in developmental defects of liver and pancreas, heterozygous mutations are associated with a predisposition to diabetes. Similarly, defects in other genes involved in cellular differentiation and development (e.g. those encoding ciliary proteins) lead to dysregulation of lipid and carbohydrate metabolism (called here collectively “liver and pancreatic diseases”, LPD).

BOLD aims to provide a significant contribution to European health by establishing a first class training programme for early career researchers who will be able to advance the LPD field working across sectors and disciplines. BOLD’s objectives include attracting the best European early career researchers into LPD research by providing carefully designed and integrated research projects and structured training delivered by the highest-quality European scientists. The programme will be underpinned by an innovative approach to the study of LPD using cutting edge technology which will advance the current ‘state of the art’ and will be transferrable to other research. Our other objective is to ensure mutual benefits of BOLD to private and public sectors involved in LPD research by high-level involvement of multiple industrial partners which will produce researchers able to develop into world leaders in the field, both in academia and in industry.

Scientific Approach

• Molecular Biology, Molecular Genetics and Genomics: Fellows will become proficient in standard techniques and will have specific experience in methods such as ChIP and data processing, deep sequencing method used to detect miRNA expression, genetic mapping and a combined genetics and genomics approach to speed up the identification of novel genes in diabetes using comparative genomics and a candidate gene approach.
• Developmental and Cell Biology: The specific techniques acquired by the fellows will include culture of pancreatic B-cells and analysis of zf ko models, embryo phenotyping using imaging technology
• As part of Transgene Technology fellows will learn transgene addition by injection of fertilized oocytes and preparation of DNA in different animal models
• Systems Biology and Metabolomics: fellows will acquire specialised bioinformatic and computational methods employed by several partners in the network and in particular analysis of large amounts of data obtained from molecular biology experiments, imaging data analysis and interpretation of large datasets containing information on chemical compounds composition in biological samples.